Lipid lowering therapy patterns and the risk of cardiovascular events in the 1-year after acute myocardial infarction in United Arab Emirates

Aim In United Arab Emirates, cardiovascular disease (CVD) is a leading cause of mortality and 22% of CVD deaths are attributable to acute myocardial infarction (MI). Adherence to guidelines for lipid management is incompletely described in the Middle East. This study aimed to characterize lipid lowering therapy (LLT) patterns and the risk of subsequent cardiovascular events (CVEs) in the first year after MI. Methods This was a retrospective cohort study using the Dubai Real-World Claims Database, including all patients discharged with MI between January 01, 2015 and December 31, 2018, followed-up until December 31, 2019. Results In the first year after MI, 8.42% of 4,595 patients included experienced at least one recurrent MI (rate 6.77 events/100 person-years [PYs]), 2.94% had one revascularization (cumulative rate 0.55 events/100 PYs) and 2.66% had one hospitalization due to unstable angina (cumulative rate 5.16 new events/100 PYs). The majority (60.40%) of the patients presented with LDL-C levels ≥ 70 mg/dL after MI. In the first year after MI, 93.45% of the patients received LLT, mainly high-intensity statin (67.79%); with a minority of patients receiving statin + ezetimibe (4.55%), PCSK9i (0.20%) or ezetimibe alone (0.07%). Conclusion Patients hospitalized with MI in Dubai present an increased risk of CVEs in their first-year post-discharge. Majority of the patients presented with LDL-C levels above 70 mg/dL, which indicates suboptimal lipid control with existing LLT, particularly in high-risk patients.

Introduction Cardiovascular disease (CVD) and the associated burden are increasing globally and represent a key challenge in healthcare. The World Health Organization has reported that CVD is the primary cause of death worldwide, accounting for 17.9 million deaths (31% of all deaths) in 2016. Over three-quarters of CVD deaths occur in low and middle-income countries [1]. The Middle East has been reported to have the highest increasing CVD-associated mortality rate in the world [2,3]. In United Arab Emirates (UAE), CVD is a leading cause of mortality and of CVD deaths, 22% were attributable to acute myocardial infarction (MI), 16% to cerebrovascular disease, 6% to ischemic heart disease and 5% to hypertension [4]. Moreover, the Gulf Registry of Acute Coronary Events and its second iteration (Gulf RACE and Gulf RACE-2) demonstrated that patients with acute coronary syndrome in the Arab Middle East are younger than in developed countries and have higher rates of diabetes and smoking [5,6].
Survivors of MI are at high-risk of cardiovascular events (CVEs) such as stroke, recurrent MI or cardiovascular death, and studies have shown this risk is higher in the first year following the index MI [7,8]. These findings reinforce the importance of both acute clinical care and secondary prevention in improving outcomes for patients with MI. Numerous studies have highlighted the importance of lowering cholesterol, specifically low-density lipoprotein cholesterol (LDL-C) in patients with cardiovascular risk [9][10][11]. Although international guidelines for managing plasma lipids exist and there is agreement on most of the key recommendations, there is, however, a lack of awareness and adherence to these guidelines by local healthcare professionals in the Middle East [2,12]. In the Africa Middle East Cardiovascular Epidemiological cross-sectional study, UAE was one of the top 5 countries with the highest prevalence of dyslipidemia (exceeding 70%) [13].
Therefore, using the Dubai Real-World Claims Database, the current study aimed to characterize the risk of subsequent CVEs in survivors of MI during the first year after index MI discharge and lipid lowering therapy (LLT) patterns (primary objective), and describe their subsequent LDL-C levels (secondary objective). The findings of this study can contribute to a better understanding of the clinical management of MI in real-world clinical practice in UAE, providing valuable evidence to inform primary and secondary prevention of CVD in this region.

Methods
This was a retrospective cohort study using the Dubai Real-World Claims Database. This database is an anonymized longitudinal patient level database of insurance claims generated from the private healthcare sector in the Emirate of Dubai. An ethics committee approval was not required for the analysis of this anonymized retrospective patient dataset. Less than 0.1% of the claims in the dataset are from the public sector. The database comprises over 10 million patients who are UAE residents and have claims for treatment from a medical facility located in Dubai. It contains information on patient demographics, diagnoses, procedures (medical, surgical, and diagnostic), prescriptions, and other related services. The database captures 100% of the population covered by private health insurance in Dubai. As, approximately 80% of the population in Dubai is covered by private insurance (predominantly comprising the expatriate community) while the remaining 20% are covered by public funding (comprising the local Emirati population), the Dubai electronic (e)-Claims are representative of the multi-ethnic population of Dubai.
This study included all adult patients with atherosclerotic cardiovascular disease (ASCVD) registered in the database. To be included in the analysis of the primary objective, patients had to fulfill all the following criteria: 1) Patients with an index event (MI) between 01st January 2015 and 31st December 2018 (study inclusion period); 2) Patients aged �18 years at index date; 3) Patients with continuous enrollment (Patients with at least one claim for any service (MI or Non-MI) during the 6-months in the pre-index period and during the 6-month in post-index period), as this criterion is a surrogate for ensuring the inclusion of patients who are registered and active with their medical practice. Patients with missing age, gender and other data quality issues were excluded from the study. To be included in the analysis of the secondary objectives, patients also had to have at least one LDL-C measurement 6-month post-index date.
MI cases were ascertained from the database using inpatient medical claims and procedure codes, and the date of the first MI record within the inclusion period was termed as the index date. The overall study period (January 2014 to December 2019) allowed at least 12-months of data pre-index period (Baseline period) and at least 12-months data post-index period (followup period) for all patients. See Supplementary Materials for further details on the methodology used (including code lists used [S1 Appendix], data transformation definitions [S2 Appendix] and handling of missing data [S3 Appendix]).
The statistical analyses were mainly descriptive. Continuous variables were summarized using standard summary statistics such as number of observations, mean and median values, standard deviation (SD). Categorical variables were summarized in frequency tables as counts and percentages of the total study population, and by subgroups where appropriate. Cumulative post-index CVE rate per 100 person-years (PYs) was calculated for all CVE types (MI, ischemic stroke [IS], unstable angina [UA], revascularization, composite of MI or IS and composite of all acute CVEs), from the index date to the end of one-year in the post-index period, using the following formula: Number of distinct CV events in all post À index period � 100 Patient À years from index to the earliest of the following : End of reporting period ð1 yrÞ

End of the Continuous Enrollment ðCEÞ
End of study period ðDecember 31; 2019Þ Table 1 presents a summary of the selection of patients to be included in this study, according to the pre-specified inclusion and exclusion criteria. A total of 4,595 patients were included in the final analysis (primary objective) and 1,740 patients were included in the analysis of postindex LDL-C levels (secondary objective). At discharge from MI hospitalization, the mean age of the patients was 52.4 years (SD 12.5 years), with the majority being male (N = 3,865; 84.11%). In the 12-months before index MI, 88.05% (N = 4,046) of the patients received LLT, mainly statins (N = 3,934; 85.61%) and those of high-intensity (N = 3,163; 68.84%) (see S1 Table for details on the classification of statins therapy intensity). A minority of patients received a combination of statin + ezetimibe (N = 108; 2.35%), 2 patients received PCSK9i and 4 patients received ezetimibe alone ( Table 2). A similar pattern of LLT use was also observed in the 90 days before MI as shown in S2 Table. In this baseline period, the most frequent ASCVD diagnoses were coronary revascularization (Percutaneous Coronary Intervention; PCI) (N = 985; 21.44%) and acute coronary syndrome (MI or UA) (N = 616; 13.41%). Most patients presented comorbid cardiovascular risk factors, such as hypertension (N = 2,959; 64.40%) and diabetes (N = 2,055; 44.72%). Similar baseline characteristics were observed for the 1,740 patients included in the analysis of the secondary objective. In the 6-months before index MI, patients presented with average LDL-C   (Table 3).

Discussion
This retrospective cohort study included 4,595 adult patients from the Dubai Real-World Claims Database, discharged with MI and followed-up to their first-year post-index MI. In the Inhibitors.
Note: Index date is included in the post-index period. First prescription in 1-month post-index period and last prescription in 12-month post-index period were used.  12 months before MI discharge, most patients presented with an ASCVD diagnosis along with comorbid cardiovascular risk factors such as hypertension, diabetes and hypercholesterolemia; which may justify the high rates of baseline LLT use, mostly high-intensity statin therapy (Table 2). These results are in line with the evidence from large-scale randomized trials showing that statin therapy reduces the risk of MACE by about one-quarter for each mmol/L reduction in LDL-C during each year (after the first) that it continues to be taken, in both ASCVD primary and secondary prevention [14].
In the first year after MI discharge, 8.42% of the patients experienced at least one recurrent MI and 12.82% experienced at least one MACE (composite rate 6.77 events/100 PYs) ( Table 3). Other studies have found that around 20% of patients with MI experience at least one MACE in the first year after index MI; approximately 12% of these patients having at least one recurrent MI [15,16]. Nonetheless, more contemporary data on MACE rates shows lower incidence rates of MACE, even in patients with established ASCVD (2.12 events/100 PYs) [17]. Therefore, the results of this study indicate that patients hospitalized with MI in Dubai present with an increased risk of MACE in their first year post-discharge, than that reported in international studies, suggesting a need for improving patient health outcomes in this region. Comparison of LDL-C levels in the pre-index and post-index periods shows reduction in LDL-C levels. We see that the % of patients in the range of better LDL-C control from <70 mg/dl to <100 mg/dl has improved drastically from 21.86% in the pre-index to 69% to postindex period. Likewise, the % of patients in the fairly poor control >100mg/dl to <190 mg/dl also reduced from 62.97% in the pre-index to 27.4% in the post-index period. The % of  Tables 5 and 6. However, if we take into consideration the goal of achieving LDL-C levels <70mg/dL to achieve good clinical outcomes, the percentage of patients who achieved <70mg/dL was not substantial (pre-index period: 7.19%; post-index period; 39.60%) (Tables 3 and 4). After their index MI, the majority (60.40%) of patients presented with LDL-C levels � 70 mg/dL (Table 4); despite most of them receiving high-intensity statin therapy, with only a minority of patients receiving a combination of ezetimibe with the statin therapy or a PCSK9 inhibitor (Tables 5 and 6).
In light of the increased rate of MACE observed in the first year after MI and given that the majority of patients presented with LDL-C levels �70 mg/dL despite most of them being on high-intensity statin therapy; our study findings underscore potential opportunities to improve clinical outcomes for patients with MI, by continued improvement in cardiac rehabilitation and optimization of LLT prescription, particularly in high-risk patients. Current guidelines emphasize on considering addition of non-statins including ezetimibe or a PCSK9 inhibitor to maximally tolerated statin therapy, in very high-risk ASCVD patients with LDL-C levels of � 70mg/dL [18]. Numerous real-world studies report failure to meet guideline recommended LDL-C levels with statin therapy alone, particularly for high-risk patients [19][20][21][22][23]. However, in line with our results, other drug utilization studies have reported that fewer than 1% of patients with ASCVD and/or heterozygous familial hypercholesterolemia added ezetimibe to statin therapy, and fewer than 1% of patients were prescribed PCSK9 inhibitors [24]. Many factors may contribute to the low rates of non-statin LLT, and the reasons for LLT initiation and changes were not investigated in this study. Nonetheless, the results from our study indicate a high-risk of CVEs during the first year post-MI discharge. These results highlight the need for better strategies to improve lipid control such as addition of non-statin therapies.
The results of this study should be interpreted in the context of its limitations. Important sources of bias should be considered in the interpretation of the results of this study: 1) Since medical conditions were identified based on existing records, coding inaccuracies may lead to misclassification bias; 2) Misclassification of LLT use is also possible since low-intensity statins may be available over the counter. However, it is likely that most prescriptions are issued in clinical care and recorded, especially among patients covered by private health insurance. In addition, it should be noted that no data were available on potential non-adherence to LLT and other lifestyle measures to improve cholesterol levels, such as a balanced diet and physical activity. As such, the effect of those factors on the observed LDL-C levels and LLT patterns is unknown. Moreover, only 37.87% (N = 1,740) of the patients had at least one LDL-C measurement in the 6-month after MI. This could represent a more intense surveillance or screening for a group of high-risk patients, and therefore introduce ascertainment bias in the interpretation of the study findings [25].
Despite these limitations, this study provides valuable evidence on the patterns of LDL-C and LLT use in the first year after MI, and the risk of subsequent MACE in survivors of MI in the Middle East. The evidence highlights the need for more aggressive treatment approaches such as augmenting statin therapy with ezetimibe or initiating PCSK9 inhibitors to achieve additional LDL-C reduction and reduce risk of recurrent MACE. The findings of this study highlight the potential to improve the clinical management of patients with MI in UAE, providing valuable evidence to inform primary and secondary prevention of ASCVD in this region. Future studies should identify barriers to suboptimal prescription of non-statin LLT and provide guidance to improve it.